Researchers have biosynthesized an anti-cancer chemical discovered in a venomous Australian tree.

Many people avoid the Australian stinging tree (Dendrocnide moroides) at all costs. The tree, a member of the nettle family, is covered in thin silicon needles laced with moroidin, one of nature’s most agonizing toxins. “It’s infamous for creating intense pain that lasts for a long time,” Whitehead Institute Member Jing-Ke Weng stated.

However, moroidin has another adverse effect: in addition to generating pain, the molecule attaches to the cytoskeletons of cells, blocking them from dividing, making moroidin a promising option for chemotherapeutic medicines.

“The tree, which is a member of the nettle family, is covered in thin silicon needles laced with one of nature’s most excruciating toxins, a compound called moroidin. It’s notorious for causing extreme pain, which lingers for a very long time,”

said Whitehead Institute Member Jing-Ke Weng.

For obvious reasons, gathering enough of the chemical to analyze has been difficult. In a paper published on April 19 in the Journal of the American Chemical Society, Weng, an associate professor of biology at the Massachusetts Institute of Technology (MIT), and former postdoc Roland Kersten, now an assistant professor at the University of Michigan College of Pharmacy, present the first published method to biosynthesize moroidin within the tissues of harmless plants such as tobacco, facilitating research on the compound’s utility for cancer treatment.

Stinging trees (left) look harmless. But their stems and petioles (middle) are covered with tiny, needle-like hairs (right) that inject venom under the skin.

Using plants as a model to generate peptides

Moroidin is a bicyclic peptide, which is a sort of molecule made up of amino acid building blocks that have been circularized to form two connected rings. Because of its complicated molecular structure, moroidin has proven to be nearly as challenging to produce as synthetic chemists. Weng and Kersten sought to learn more about the processes that plants use to produce this chemical.

Cyclic peptides are formed in plant cells from specific precursor proteins synthesized by the ribosome, a macromolecular mechanism that generates proteins by translating messenger RNAs. After leaving the ribosome, these precursor proteins are further processed in the cell by additional enzymes to produce the final cyclic peptides. In 2018, Weng and Kersten discovered the biosynthesis mechanism of another sort of plant peptide called lyciumins, which gave them some insight into how post-translational alterations can play a role in producing diverse types of plant peptide chemistry. By studying lyciumins, we learned a lot about the main components of this system, Weng added.

When the researchers started looking into how moroidin was made, they discovered that a few other plants, such as Kerria japonica and Celosia argentea, produce peptides with similar chemistry to moroidin.”That truly provided us with the essential understanding that this is a new class of peptides,” Weng added.

Weng and Kersten previously discovered that the BURP domain, which is found in the precursor proteins for lyciumins and other plant cyclic peptides, catalyzes crucial processes involved in the synthesis of peptide rings. They discovered that the BURP domain was present in the precursor proteins for moroidins in Kerria japonica and appeared to be required for the molecules’ two-ring shape. When the BURP domain is exposed to copper, it produces ring chemistry, and when the researchers treated the moroidin precursor protein with copper chloride in the lab alongside other downstream proteolytic enzymes, they were able to produce moroidin-like peptides.

They were able to develop a number of moroidin analogs in tobacco plants using this information by transgenically expressing the moroidin precursor gene of Kerria japonica and altering the core motif sequence matching to moroidin peptides. Weng explained that “we show that the same moroidin chemistry may be produced in a different host plant.” “We hope in the future we can develop a plant cell line from the existing tobacco cell lines that we put in the moroidin precursor peptide. Then we can use the cell line to produce the molecule, which really enables us to scale up for pharmaceutical production.”

Moroidin’s future applications

The anti-cancer function of moroidin is attributable, at least in part, to the compound’s unusual structure, which allows it to connect to a protein called tubulin. Tubulin serves as a skeletal framework for live cells, allowing cells to separate their chromosomes as they prepare to divide. Vincristine and paclitaxel, two established anti-cancer medicines, act by binding to tubulin. These two chemicals are also obtained from plants (the Madagascar periwinkle and the Pacific yew tree, respectively).

In their latest study, Weng and Kersten created celogentin C, a moroidin mimic. They evaluated the compound’s anti-cancer properties against a human lung cancer cell line and discovered that it was harmful to the cancer cells. In addition to tubulin inhibition, their current discovery suggests potentially new anti-cancer pathways specific to this lung cancer cell line.

In the past, researchers have encountered difficulties in developing useful medications using peptides. “Peptides as medication face two fundamental obstacles,” Weng explained. For one thing, they are not very stable in vivo, and for another, they are not particularly bioavailable and do not readily pass through a cell’s membrane.”

However, cyclic peptides such as moroidin and its analogs are not the same. Essentially, these peptides evolve to be drug-like, Weng explained. The peptides are present in the Australian stinging tree because the plants seek to prevent animals from eating the leaves. So, after millions of years of evolution, these plants worked out how to build these precise cyclic peptides that are stable, bioavailable, and can reach the animal that is attempting to eat the plants.

The unpleasant reaction that happens when moroidin enters the body from a sting from the tree is unlikely to be an issue in typical chemotherapy administration methods. Weng explained, “The discomfort is really caused when the substance is injected into the skin.” “Your body will most likely not feel the pain if you take it orally or intravenously.”

Surprisingly, the chemical could also be utilized as a pain reliever. Sometimes, if something produces pain, you can utilize it as an anti-pain drug, Weng explained. “You could effectively exhaust the pain receptors, or you could change the structure slightly and turn an agonist into an antagonist, potentially blocking the pain.”

On a more fundamental level, moroidin could aid researchers in their research into pain receptors. We don’t know why getting stung by the stinging tree causes such intense pain, and there may be other pain receptors that haven’t been identified yet, Weng added. “The ability to make moroidin provides us with a chemical probe that allows us to explore this unknown pain perception in humans.”

In the future, the researchers plan to develop moroidin analogs to analyze and, eventually, develop an optimal form for use in cancer therapy. Weng explained that “we’d like to create a library of moroidin-like peptides.” Because the original moroidins are anti-tubulin molecules, we can use this system to develop an enhanced version that binds to tubulin even tighter and has other pharmacological features that make it acceptable for use as a treatment.

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